The regulation of p53 up-regulated modulator of apoptosis by JNK/c-Jun pathway in β-amyloid-induced neuron death
The regulation of p53 up-regulated modulator of apoptosis by JNK/c-Jun pathway in β-amyloid-induced neuron death
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DOI：
10.1111/jnc.13128
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发表时间：
2015-09-01
影响因子：
4.7
通讯作者：
Biswas, Subhas Chandra
中科院分区：
文献类型：
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作者：
Akhter, Rumana;Sanphui, Priyankar;Biswas, Subhas Chandra
阿尔茨海默病(AD)的病理基础是大脑选择性区域的神经元丢失。最近的证据表明，寡聚体β-淀粉样蛋白(Aβ)是该病的中心。然而，神经元对Aβ反应的死亡机制仍然不清楚。据报道，c-Jun氨基末端激酶(JNK)通路的激活和AP-1转录因子c-Jun的诱导在AD发病中起重要作用。然而，JNK/c-Jun在Aβ诱导的神经元死亡中的靶点大多是未知的。我们的研究表明，促凋亡蛋白Bim(细胞死亡的相互作用介质)和PUMA(P53上调的凋亡调节因子)是Aβ处理的神经元中c-Jun的靶点。我们证明，在用寡聚Aβ处理皮层神经元的培养中和AD转基因小鼠中，JNK/c-Jun途径被激活，并且选择性抑制剂抑制这一途径可以阻断Aβ诱导的Puma。我们还发现，JNK和P53通路都协同调节Aβ处理的神经元中Puma的表达。此外，我们在大鼠PUMA基因上发现了一个新的AP1结合位点，这是c-Jun与PUMA启动子直接结合所必需的。最后，我们发现siRNA下调c-jun对Aβ毒性具有显著的保护作用，而Aβ诱导神经元中的Bim和Puma需要c-jun。综上所述，我们的结果表明Bim和Puma都是c-Jun的靶点，并阐明了在Aβ毒性作用下，JNK/c-Jun和P53信号通路对PUMA表达的复杂调控。
Neuronal loss in selective areas of brain underlies the pathology of Alzheimer's disease (AD). Recent evidences place oligomeric beta-amyloid (A beta) central to the disease. However, mechanism of neuron death in response to A beta remains elusive. Activation of the c-Jun N-terminal kinase (JNK) pathway and induction of the AP-1 transcription factor c-Jun are reported in AD. However, targets of JNK/c-Jun in A beta-induced neuron death are mostly unknown. Our study shows that pro-apoptotic proteins, Bim (Bcl-2 interacting mediator of cell death) and Puma (p53 up-regulated modulator of apoptosis) are targets of c-Jun in A beta-treated neurons. We demonstrate that the JNK/c-Jun pathway is activated, in cultures of cortical neurons following treatment with oligomeric A beta and in AD transgenic mice, and that inhibition of this pathway by selective inhibitor blocks induction of Puma by A beta. We also find that both JNK and p53 pathways co-operatively regulate Puma expression in A beta-treated neurons. Moreover, we identified a novel AP1-binding site on rat puma gene which is necessary for direct binding of c-Jun with Puma promoter. Finally, we find that knocking down of c-Jun by siRNA provides significant protection from A beta toxicity and that induction of Bim and Puma by A beta in neurons requires c-Jun. Taken together, our results suggest that both Bim and Puma are target of c-Jun and elucidate the intricate regulation of Puma expression by JNK/c-Jun and p53 pathways in neurons upon A beta toxicity.